To date, tooth remineralisation is achieved mainly by the delivery of calcium and phosphate ions into tooth lesions or cavities. The calcium and phosphate ions are usually included in tooth pastes which also contain e.g. abrasives, fluorides, surfactants and other remineralisation agents. The calcium and phosphate ions may be used in various crystalline forms, e.g. as hydroxyapatite-based materials, or as amorphous calcium phosphate, such as in some Recaldent-based materials.
More recently, an alternative approach of tooth remineralisation has been described which is based on short rationally designed self-assembling peptides. WO 2004/007532 discloses peptides that are capable of forming three-dimensional scaffolds, thereby promoting nucleation of de-novo calcium phosphate. These artificial peptides assemble in one dimension to form beta-sheet, tape-like assemblies. The peptide assemblies can switch from a fluid to a nematic, stiffer gel state in response to chemical or physical triggers. The peptides were designed to form assemblies in response to certain pH, ionic strength and/or temperature conditions in the following hierarchical order: tapes, ribbons, fibrils and fibres. Aggeli et al. (2003, J. Am. Chem. Soc. 125, 9619-9628) analyses pH as a trigger of peptide beta-sheet self-assembly.
Several other self-assembling peptides have been described in the prior art. For example, WO 2010/041636 A1 describes a bioadsorbable peptide tissue occluding agent containing an artificial peptide having 8-200 amino acid residues with the hydrophilic amino acids and hydrophopbic amino acids alternately bonded, which self-assembles into a beta-structure at physiological pH. Self-assembling peptides with alternating hydrophobic and hydrophilic residues or stretches which interact with the extracellular matrix are also disclosed in WO 2008/113030 A2. WO 2010/103887 A1 discloses self-assembling peptides, which comprise basic, hydrophobic and acidic amino acids of a specific primary sequence and peptide gels thereof which have high strength.
Another application, WO 2007/000979 A1, describes self-assembling peptides with polar and non-polar amino acids. The peptides are capable of forming a beta-sheet structure in which the non-polar amino acid residues are arranged on one side of the structure in the assembled form. Amphiphilic self-assembling peptides for use as stable macroscopic membranes, which are used in biomaterial applications, such as slow-diffusion drug delivery, are described in U.S. Pat. No. 6,548,630.
EP 2 327 428 A2 refers to a pharmaceutical composition comprising self-assembling peptide nanofibers, which are complementary to each other, and at least one cell for repairing damaged tissue, such as tissue after a myocardial infarction.
The use of self-assembling peptides for the delivery of bioactive agents has also been described in the prior art, for example in US 2008/199431 A1 and in WO 2009/026729 A1. WO 2006/073889 A2 relates to a composition in which human PDGF is bound directly to peptides which assemble into a gel that slowly releases PDGF in vivo. WO 2006/047315 A2 proposes the attachment of therapeutic agents to self-assembling peptides using biotin/streptavidin linkages.
Kirkham et al. relates to self-assembling peptide scaffolds promoting enamel remineralisation (2007, Dent. Res. 86(5), 426-430).
As can be seen from the above, several self-assembling peptides have been described that can be used as templates or scaffolds in tooth remineralisation for in situ nucleation of calcium phosphate. However, a particular problem that one may encounter in tooth remineralisation is that subsurface lesions may be inaccessible for the assembled form of the peptides. Once these peptides have formed tapes, ribbons, fibrils or fibres, the size of the assemblies is such that diffusion into the subsurface lesion through small pores in the hypermineralised plate on the tooth surface is no longer possible in an amount necessary to achieve a significant effect.
Thus, to effectively treat subsurface lesions, the self-assembling peptide needs to be in a monomeric form outside the tooth lesion to enable diffusion into the subsurface lesion, and it needs to switch into a fibrillar form once inside the tooth lesion. If the peptides assemble outside the lesion, it cannot facilitate remineralisation within the lesion, as the formed three-dimensional structures are too large to diffuse through the pores.
Several drug transfer devices have been described in the prior art. For example, fluid transfer devices with sealing arrangements for direct application of drugs have been disclosed (e.g. WO 2011/058545 A1, WO 2011/104711 A1). However, none of these drug transfer devices eliminates the problem of assemblies outside a tooth lesion.